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newer antibiotics.pptx
- 1. Newer Antibacterials Dr. SubodhGyawali Internal medicine resident 1st year
- 2. History • Alexander Flemingdiscovered Penicillin 1928 • Domagk discovered Sulphonamides 1935 • Selman Waksman discovered Streptomycin 1943 • G.Brotzu discovered Cephalosporins 1945 • Macrolides 1952 • George Lesher and coworkers fluoroquinolones 1962
- 3. Between 1962 and2000, no major classes of antibiotics were introduced
- 4.
- 5. Oxazolidinones • Considered tobe the first truly new class of antibacterial drugs introduced in the past 3 decades • Linezolid- Approved for adults use in 2000, approved for pediatric use in 2005 • Tedizolid – Approved for adult use in 2014.
- 6. Linezolid MOA: inhibit proteinsynthesis by binding to 50 S subunit and preventing formation of the initiation complex Bioavailability: 100% Half life: 4-5 hrs Excretion: hepatic Use: Gram +ve species including MRSA and VRE. S/E: bone marrow suppression( esp. thrombocytopenia), peripheral neuropathy, serotonin syndrome, optic neuritis Mech. of resistance: point mutation of ribosomal RNA Dose : 600 mg iv/oral twice a day
- 7. Tedizolid • Similar tolinezolid • FDA approved for >12 yrs of age • Bioavailability: 91% • Half life : 12 hrs • Elimination : 82% faecal, 18 % urine • Dose : 200mg IV/oral once a day.
- 8. Newer Oxazolidinones • Radezolid-Phase II clinical trial Uncomplicated skin and skin structure infections • Torezolid -Phase II clinical trial Complicated skin and skin structure infections MOA: Bind to the 23S portion of the 50S subunit preventing translation initiation Advantage over linezolid : Improved potency, Aqueous solubility, Reduced toxicity, overcomes resistance by additional hydrogen bond interactions with 23S rRNA
- 9. Newer glycopeptides • Telavancin: Approved in 2009 for complicated skin and skin structure infections(MRSA) • Dalbavancin : Approved in 2014. • Oritavancin : Approved in 2014.
- 10. • MOA: Inhibitspeptidoglycan biosynthesis by inhibiting transglycosylation + transpeptidation • Additional mode of action shown by newer drugs- • Causes disruption of membrane potential • Increases cell permeability causing rapid bactericidal activity • Dalbavancin, oritavancin, and telavancin half lives in humans are approximately 7 days, 15 days, and 7.5 hrs respectively • Excretion : renal
- 11. Advantage over Vancomycin •Additional mechanisms of action • Rapid bactericidal activity against Vancomycin Resistant Enteroccoci (VRE) and VRSA, unlike vancomycin which is bacteriostatic. • More potent and lesser potential for resistance • Less frequent dosing • Longer t 1/2 life
- 12. Lipopeptides • Developed forthe treatment of vancomycin-resistant enterococcal infections • Daptomycin- approved by FDA in 2003 for the treatment of SSTIs and approved in 2006 for the treatment of blood stream infections • MOA: inserting its lipophilic tail into the cell membrane of gram-positive organisms This calcium dependent process leads to the formation of channels from which intracellular potassium is lost disrupting the bacterial cell membrane potential and causing cell death.
- 13. • Half life:8 hrs • Excretion: renal • Bactericidal against Methicillin resistant staphylococcus aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis and VRE inclusive of linezolid-resistant isolates. • In July 2010, a warning was issued by FDA about the potential of daptomycin to cause life threatening complication i.e., eosinophilic pneumonia
- 14. Ketolides • Semisynthetic 14membered ring macrolides • Carbonyl group at the C3 position, responsible for sensitivity to macrolide resistant strains • Telithromycin- Approved in 2004 • Cethromycin- Phase III trials • Solithromycin- Phase III trials
- 15. Telithromycin • First ketolideantibiotic to enter clinical use • Approved by the FDA in 2004 • For community acquired pneumonia: 800 mg OD for 7-10 days. • Excretion in urine and faeces. • Half life. : 10 hrs
- 16. Glycylcyclines • New classof antibiotics derived from tetracycline • Designed to overcome two common mechanisms of tetracycline resistance resistance mediated by • acquired efflux pumps , • ribosomal protection • TIGECYCLINE : approved in 2005 • PTK0796(Omadacycline) : approved in 2018
- 17. Tigecycline • Approved in2005 • MOA: Acts by binding to 30-S subunit of ribosome, thus inhibiting protein synthesis which is 20 fold more efficient than tetracycline. • Indication: Complicated skin and skin structure infections & Intra-abdominal infections. New Delhi metallo-β-Lactamase producing Enterobacteriaceae has also shown susceptibility to tigecycline. Also active against MRSA
- 18. • DOSE: OnlyI/V formulation available. Slow I/V infusion of 100 mg followed by maintenance dose(50 mg BD) • No dose adjustment in renal failure (in comparison to tetracycline) Primary route of elimination is the biliary excretion so dose adjustment is recommended in hepatic disease. • Half-life : 27 hrs.
- 19. Eravacycline Approved in 2018 •Disrupts protein synthesis by binding to 30 S ribosomal subunit • Structural changes overcomes the tetracycline resistance mechanisms.
- 20. Newer carbapenems • Beta-lactamantibiotics with a broad spectrum of antibacterial activity Ertapenem: Approved in 2001 Doripenem :Approved in 2007 ,Suitable alternative to currently available antipseudomonal carbapenems (i.e, imipenem, meropenem) Razupenem: Phase II clinical trial
- 21. Doripenem • Indication: Complicatedurinary tract infections , Intra-abdominal infections • MOA: Bind to penicillin binding proteins (PBPs) and inhibit crosslinking of the peptidoglycan structure • Half life: 1 hr • Excretion : renal • The most common ADRs are headache, nausea, diarrhea, rash, and phlebitis. Postmarketing reports have also identified Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonia, and seizures as adverse drug reactions
- 22. • Advantage : 1.Spectrumof activity similar to that of meropenem against gram-ve & similar to imipenem against gram+ve bacteria 2. Slightly better in vitro activity against P. aeruginosa 3. Not degraded by renal dehydropeptidase Dose: Available as I/V formulation only 500mg by I/V infusion every 8 hours
- 23. • Ertapenem Long halflife carbapenem Once daily dosing High protein binding Not for P. aeruginosa Low toxicity
- 24. Newer cephalosporins • Ceftaroline: •Approved in 2010 • It is a novel broad-spectrum antibiotic effective against Methicillin Resistant Staphylococcus aureus (MRSA), penicillin and cephalosporin resistant S. pneumoniae, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA). • It is also active against many gram-negative pathogens but inactive against extended-spectrum β-lactamase (ESBL) producing bacteria • acts by binding to penicillin binding proteins 1-4 (PBPs 1-4)
- 25. • half-life (t½)of 1.6 hr (for a single dose) to 2.7 hr (following multiple doses) • It is given as 600 mg intravenous dose, every 12 hourly. • Dose adjustment is required in patients with renal impairment as it is primarily eliminated by the kidneys • The most common side effects observed during clinical trials were nausea, dysgeusia and caramel-like taste disturbances, vomiting, diarhoea and headache.
- 26. Ceftobiprole • Is awaitingFDA approval due to additional safety data being demanded by FDA. • It is the broad-spectrum antibiotic which shows good spectrum of activity against MRSA, penicillin-resistant S. pneumoniae, P. aeruginosa and Enterococci.
- 27. Cefiderocol • Siderophore conjugatedcephalosporin approved in 2019
- 28. Novel Dihydrofolate reductaseinhibitors • Iclaprim • Diaminopyrimidine that inhibit DNA/RNA synthesis • Awaiting FDA approval • Indication: For the treatment of complicated skin and soft tissue infections caused by antibiotic-resistant bacteria • Designed to overcome trimethoprim resistance • Active against MRSA, penicillin resistant S. pneumoniae
- 29. Pleuromutilins • Newer classof antibiotic • MOA: Bind to 50S subunit of ribosomes inhibiting protein synthesis • Retapamulin: Approved in 2007, topical antibiotic used in treatment of skin infections such as impetigo S. aureus (methicillin-susceptible only) or S. pyogenes • Lefamulin approved in 2019 for treatment of community acquired bacterial pneumonia.
- 30. Macrocyclic antibiotic drugs. •Fidaxomicin • Narrow spectrum bactericidal agent • Alternative to the currently used treatment regimens of vancomycin and metronidazole against Clostridium difficile , approved in 2011. • MOA: Inhibit bacterial enzyme RNA polymerase • Dose : 200 mg po twice daily.
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- 32.
- 33. Meropenem and vaborbactam •Approved in 2017
- 34. Plazomycin • An aminoglycosideapproved in 2018. • MOA : binds to 30S subunit inhibiting protein synthesis • Not inhibited by most aminoglycoside modifying enzymes • Activity against enterobacteriaceae in the presence of class A and D beta-lactamases • May have reduced activity against enterobacteriaceae that overexpresses efflux pumps or lower expression of porins • No activity against acinetobacter sp and variable activity v. P. aeruginosa.
- 35.
- 36. Imipenem, cilastin andrelebactam (approved in 2019)
- 37. Take home message •There is a great need of newer antibiotics because of increasing microbial resistance • Because of increase cost of development and increasing resistant, only few drugs are in pipeline • Some of the newer agents are effective against resistant strains • Programs like Antibiotic stewardship can be helpful to combat the resistance • Rational use of antibiotics remains the most important measure
- 38. References • Newer antibacterialsin therapy and clinical trials - PubMed (nih.gov) • Antibiotics in the clinical pipeline in October 2019 | The Journal of Antibiotics (nature.com) • Bertram Katzung, Anthony Trevor - Basic and Clinical Pharmacology-Mc Graw Hill LANGE
- 39.
Editor's Notes
- #12 Mechanisms of resistance to older glycopeptide Synthesis of low-affinity precursors in which Cterminal D-Ala residue is replaced by: D-lactate (D-Lac)or by D-serine (D-Ser) Resistance overcome by: High binding affinity for both substrates(D-Ala-D-Lac precursor substrate OR D-Ala-D-Ala) due to presence of hydrophobic side chain
- #16 On 12 February 2007, FDA withdrew two of its indications(chronic bronchitis and sinusitis) with CAP as the only remaining indication, with a black‑box warning issued due to its safety concerns involving hepatotoxicity, myasthenia gravis exacerbation, and visual disturbances.[35
- #18 Tigecycline has a broader spectrum of activity against aerobic and anaerobic gram‑negative and positive pathogens. In vitro data shows that tigecycline has very good antibacterial activity against ESBL as well. It is not active against P. aeruginosa, which is an important gap in its antimicrobial spectrum.[27]
- #25 It shows high affinity for PBP2a present in Staphloccocus aureus, which is responsible for methicillin resistance. In S. pneumonia, ceftaroline can bind to all six PBPs identified (PBP1A, 1B, 2x, 2A/B, and 3) Inside the blood circulation, ceftaroline fosamil (prodrug) is rapidly converted to ceftaroline (active form) by phosphatase enzymes. Ceftaroline is metabolized by hydrolysis of its β‑lactam ring which results into the formation of an inactive, open‑ring metabolite called as ceftaroline M‑1. It has a low potential for drug interactions because of insignificant metabolism by CYP450 enzymes.
- #31 . In a phase III trial (n = 1000), fidaxomicin 200 mg (twice a day) was found to be non‑inferior to vancomycin 125 mg (four times a day) for the treatment of initial or first recurrences of CDI. Recurrence rates of CDI with fidaxomicin were significantly lower(13%) as compared to vancomycin (25%).[4]